PROJECT 2 During the last funding period, we demonstrated that programmable pump delivery of GDNF promotes improvements in motor and nigrostriatal dopamine (DA)functions in nonhuman primate models of Parkinson's disease (PD). In the proposed studies, Project 2 will use behavioral and functional magnetic resonance imaging (fMRI) methods to determine conditions to further enhance GDNF actions on motor arid DA functions in MPTP-lesioned rhesus monkeys, which best simulate the human parkinsonian state. In conjunction with Projects 1 &3, Project 2 will determine if combined putamenal and nigral delivery of GDNF, via programmable pumps and intraparenchymal catheters, will produce better behavioral recovery of the nigrostriatal pathway than single-site putamenal delivery alone. Project 2 will also investigate if chronic, intraparenchymal delivery of GDNF will more completely, restore motor and DA functions in MPTP-lesioned animals expressing milder, but stable parkinsonism versus severely impaired animals. In Project 2, the animals will be quantitatively characterized with apomorphine and levodopa/carbidopa, pre- and post-GDNF administration. To this end, we will use a variety of behavioral measurements, including: 1) an automated video-tracking system for analyzing whole body movements, 2) an automated hand-retrieval task for evaluating fine hand/coarse arm movements, and 3) a nonhuman primate rating scale for evaluating behavioral features characteristic of PD: bradykinesia, rigidity, posture, balance and tremor. In addition to behavioral testing, Project 2 will use fMRI techniques to noninvasively and simultaneously measure apomorphine-evoked blood oxygen level-dependent (BOLD) changes in basal ganglia functions of alert rhesus monkeys, pre- and post-GDNF administration. Collectively, these studies should contribute to an improved mechanistic understanding of the effects of chronic GDNF treatment on the nigrostriatal DA system in nonhuman primates and improved approaches for the treatment of PD.